bims-stacyt 2025-02-09 papers

Biochim Biophys Acta Mol Basis Dis. 2025 Jan 31. pii: S0925-4439(25)00047-X. [Epub ahead of print] 167702

Hypoxic stress promotes astrocyte infiltration-like growth via HIF-1α/GDNF/LOXL2 axis.

Zimu Li, Shun Xi, Ziqi Zhang, Xugang Kan, Yang Zhang, Miaomiao Wang, Yudong Wang, Yefeng Shi, Haoyue Xu, Baole Zhang.

Elevated levels of glial cell line-derived neurotrophic factor (GDNF) are implicated in the transformation of astrocytes into astrogliomas, but the underlying mechanisms are not fully understood. In this study, we found that hypoxia led to a significant increase in GDNF expression in primary rat astrocytes from various brain regions, including the cortex, hippocampus, and corpus callosum. This was accompanied by the activation of astrocytes, particularly those of the A2 subtype, and a concurrent increase in hypoxia-inducible factor 1-alpha (HIF-1α) expression. The elevated levels of HIF-1α enhanced its binding to the GDNF promoter, resulting in increased GDNF expression. Interestingly, this process formed a positive feedback loop, as elevated GDNF further activated HIF-1α in primary rat and human astrocytes. Furthermore, lysyl oxidase-like protein 2 (LOXL2), a novel downstream oncogene of GDNF, showed a significant increase following hypoxia treatment and exhibited a positive correlation with GDNF expression. Inhibiting GDNF signaling effectively suppressed this expression. Hypoxia-induced GDNF also increased the phosphorylation of ERK, P38, and CREB through the classical GDNF receptors, GFRα1 and RET. This led to increased binding of phosphorylated CREB to the LOXL2 promoter, resulting in enhanced LOXL2 expression. Consequently, rat astrocytes under hypoxic stress exhibited increased cell viability, migration, and epithelial-mesenchymal transition, which were mitigated by inhibiting GDNF signaling or silencing LOXL2. This phenomenon was also observed in C6 cells. Our findings suggest that hypoxia induces astrocyte activation and upregulates LOXL2 expression through the HIF-1α/GDNF/P-CREB signaling axis, facilitating the infiltration-like growth of astrocytes and the infiltrative growth of C6 astroglioma cells.

Keywords: Astrocyte; Astroglioma; GDNF; Hypoxia; LOXL2

DOI: https://doi.org/10.1016/j.bbadis.2025.167702

J Nutr Health Aging. 2025 Feb 03. pii: S1279-7707(25)00016-8. [Epub ahead of print]29(4): 100493

Serum Growth Differentiation Factor 15 is Negatively Associated with Leukocyte Telomere Length.

Jie Yu, Yiwen Liu, Huabing Zhang, Fan Ping, Wei Li, Lingling Xu, Yuxiu Li.

BACKGROUND: Telomere length(TL)and mitochondrial DNA copy number(mtDNAcn) are classic biomarker of aging. Recently, growth differentiation factor 15(GDF15) has attracted considerable attention as a vital component in the aging process.
METHODS: The present study aimed to study the relationship between GDF15 and telomere length and mtDNAcn.This was a cross-sectional analysis nested in a longitudinal cohort study conducted in Changping District, Beijing, from 2014 to 2021. Serum GDF15,leukocyte lelomere length(LTL) and mtDNAcn were determined in 802 subjects.LTL and mtDNAcn was quantified by real-time PCR assay. Multivariate linear regression and restricted cubic spline diagram were used for statistical analysis.
RESULTS: Subjects with higher GDF15 were older,had larger waist circumference, higher systolic blood pressure and glycated hemoglobin A1c (HbA1c),shorter LTL and tended to had less mtDNAcn. In correlation analysis, GDF15 was positively correlated with age, while LTL and mtDNAcn were negatively correlated with age.After adjusting for confounding factors,GDF15 was negatively associated with LTL (β = -0.120, 95%CI [-0.197, -0.042], p = 0.003) and the association was linear(p for nonlinear = 0.645), while the negative association between GDF15 and mtDNAcn did not reach significance.In the stratified analyses,the negative associations between GDF15 and LTL were more prominent in women, overweight individuals, or subjects with abnormal glucose tolerance (AGT), but similar results were observed in younger and older subjects.
CONCLUSIONS: This study found a linear negative association between GDF 15 and LTL,which was more prominent in women, overweight or AGT subjects.These results supported that GDF15 might be a reliable biomarker of aging.

Keywords: Aging; Growth differentiation factor 15; Leukocyte telomere length; Mitochondrial DNA copy number

DOI: https://doi.org/10.1016/j.jnha.2025.100493

J Neurosci. 2025 Feb 07. pii: e1406242025. [Epub ahead of print]

TIGAR suppresses ER stress-induced neuronal injury through targeting ATF4-signaling in cerebral ischemia/reperfusion.

Lei Chen, Jie Tang, Xue-Qing Liu, Qi-Qi Li, Jia-Ying Li, Yan-Yan Li, Wen-Hua Zheng, Zheng-Hong Qin, Rui Sheng.

Endoplasmic reticulum (ER) stress is crucial in cerebral ischemia/reperfusion injury by triggering cellular apoptosis and exacerbating neuronal damage. This study elucidates the dynamics of TP53-induced glycolysis and apoptosis regulator (TIGAR) translocation and its role in regulating neural fate during cerebral ischemia-induced ER stress, specifically in male mice. We found enhanced nuclear localization of TIGAR in neurons after transient middle cerebral artery occlusion/reperfusion (tMCAO/R) in male mice, as well as oxygen glucose deprivation/reperfusion (OGD/R) and treatment with ER stress inducer (tunicamycin and thapsigargin) in neuronal cells. Conditional neuronal knockdown of Tigar aggravated the injury following ischemia-reperfusion, whereas overexpression of Tigar attenuated cerebral ischemic injury and ameliorated intra-neuronal ER stress. Additionally, TIGAR overexpression reduced the elevation of ATF4 target genes and attenuated ER stress-induced cell death. Notably, TIGAR co-localized and interacted with ATF4 in the nucleus, inhibiting its downstream pro-apoptotic gene transcription, consequently protecting against ischemic injury. In vitro and in vivo experiments revealed that ATF4 overexpression reversed the protective effects of TIGAR against cerebral ischemic injury. Intriguingly, our study identified the Q141/K145 residues of TIGAR, crucial for its nuclear translocation and interaction with ATF4, highlighting a novel aspect of TIGAR's function distinct from its known phosphatase activity or mitochondrial localization domains. These findings reveal a novel neuroprotective mechanism of TIGAR in regulating ER stress through ATF4-mediated signaling pathways. These insights may guide targeted therapeutic strategies to protect neuronal function and alleviate the deleterious effects of cerebral ischemic injury.Significance statement TIGAR (TP53-induced glycolysis and apoptosis regulator) is one of the downstream target genes of p53, and its encoded protein exerts Fru-2, 6-BPase activity to promote glucose metabolic flux to pentose phosphate pathway. However, the non-enzymatic function of TIGAR has been gradually discovered. Here, we demonstrate that TIGAR translocates to the nucleus to interact with ATF4 in neurons after cerebral ischemia/reperfusion induced ER stress via its Q141/K145 residues. Then TIGAR inhibits ATF4's downstream pro-apoptotic genes expression, reduces ER stress-dependent apoptosis, consequently alleviating neuronal damage. This study uncovered a novel neuroprotective mechanism of TIGAR by regulating ER stress via ATF4-mediated signaling pathway. The Q141/K145 residues of TIGAR are critical for its interaction with ATF4 and inhibition of ATF4 target genes.

DOI: https://doi.org/10.1523/JNEUROSCI.1406-24.2025